TDP-43 pathology in Drosophila induces glial-cell type specific toxicity that can be ameliorated by knock-down of SF2/SRSF1

Krupp, Sarah; Hubbard, Isabel; Tam, Oliver; Hammell, Gale M.; Dubnau, Josh

doi:10.1371/journal.pgen.1010973

Cited by 2 publications

(1 citation statement)

References 74 publications

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“…Here, we used Drosophila to assess sleep in protein expression models of human neurodegenerative disease. We found that directed expression of TDP-43, which is an established model for ALS/FTD ( 24 , 47 , 54 – 57 ), led to severe sleep deficits. Depletion of Ataxin-2 ( Atx2 ), a modifier of TDP-43 toxicity in flies and mice ( 45 , 58 , 59 ), reversed the TDP-43 sleep phenotype.…”

Section: Introductionmentioning

confidence: 87%

TDP-43 impairs sleep in Drosophila through Ataxin-2 –dependent metabolic disturbance

Perlegos,

Durkin,

Belfer

et al. 2024

Sci. Adv.

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Neurodegenerative diseases such as amyotrophic lateral sclerosis and frontotemporal dementia are associated with substantial sleep disruption, which may accelerate cognitive decline and brain degeneration. Here, we define a role for trans-activation response element (TAR) DNA binding protein 43 (TDP-43), a protein associated with human neurodegenerative disease, in regulating sleep using Drosophila . Expression of TDP-43 severely disrupts sleep, and the sleep deficit is rescued by Atx2 knockdown. Brain RNA sequencing revealed that Atx2 RNA interference regulates transcripts enriched for small-molecule metabolic signaling in TDP-43 brains. Focusing on these Atx2 -regulated genes, we identified suppressors of the TDP-43 sleep phenotype enriched for metabolism pathways. Knockdown of Atx2 or treatment with rapamycin attenuated the sleep phenotype and mitigated the disruption of small-molecule glycogen metabolism caused by TDP-43. Our findings provide a connection between toxicity of TDP-43 and sleep disturbances and highlight key aspects of metabolism that interplay with TDP-43 toxicity upon Atx2 rescue.

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Section: Introductionmentioning

confidence: 87%

TDP-43 impairs sleep in Drosophila through Ataxin-2 –dependent metabolic disturbance

Perlegos,

Durkin,

Belfer

et al. 2024

Sci. Adv.

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ALS molecular subtypes are a combination of cellular, genetic, and pathological features learned by deep multiomics classifiers

O’Neill,

Shaw,

Bolger

et al. 2024

Preprint

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Amyotrophic Lateral Sclerosis (ALS) is a complex syndrome with multiple genetic causes and wide variation in disease presentation. Despite this general heterogeneity, several common factors have been identified. For example, nearly all patients show pathological accumulations of phosphorylated TDP-43 protein in affected regions of the motor cortex and spinal cord. Moreover, large patient cohort studies have revealed that most patient samples can be grouped into a small number of ALS subtypes, as defined by their transcriptomic profiles. These ALS molecular subtypes can be grouped by whether postmortem motor cortex samples display signatures of: mitochondrial dysfunction and oxidative stress (ALS-Ox), microglial activation and neuroinflammation (ALS-Glia), or dense TDP-43 pathology and associated transposable element de-silencing (ALS-TE). In this study, we have built a deep layer ALS neural network classifier (DANcer) that has learned to accurately assign patient samples to these ALS subtypes, and which can be run on either bulk or single-cell datasets. Upon applying this classifier to an expanded ALS patient cohort from the NYGC ALS Consortium, we show that ALS Molecular Subtypes are robust across clinical centers, with no new subtypes appearing in a cohort that has quadrupled in size. Signatures from two of these molecular subtypes strongly correlate with disease duration: ALS-TE signatures in cortex and ALS-Glia signatures in spinal cord, revealing molecular correlates of clinical features. Finally, we use single nucleus RNA sequencing to reveal the cell type-specific contributions to ALS subtype, as determined by our single-cell classifier (scDANCer). Single-cell transcriptomes reveal that ALS molecular subtypes are recapitulated in neurons and glia, with both ALS-wide shared alterations in each cell type as well as ALS subtype-specific alterations. In summary, ALS molecular subtypes: (1) are robust across large cohorts of sporadic and familial ALS patient samples, (2) represent a combination of cellular, genetic, and pathological features, and (3) correlate with clinical features of ALS.Abstract FigureFigure 0:Graphical Abstract - ALS molecular subtypes are a combination of cellular, genetic, and pathological features learned by deep multiomics classifiers.

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TDP-43 pathology in Drosophila induces glial-cell type specific toxicity that can be ameliorated by knock-down of SF2/SRSF1

Cited by 2 publications

References 74 publications

TDP-43 impairs sleep in Drosophila through Ataxin-2 –dependent metabolic disturbance

TDP-43 impairs sleep in Drosophila through Ataxin-2 –dependent metabolic disturbance

ALS molecular subtypes are a combination of cellular, genetic, and pathological features learned by deep multiomics classifiers

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